AZD5069: Pharmacological profile of a CXCR2 antagonist in development for the treatment of respiratory disorders

Background: Neutrophil-driven inflammation is a key component in inadequately controlled asthma, COPD and bronchiectasis. Neutrophil migration into the lung is predominantly controlled by C-X-C chemokine receptor 2 (CXCR2). AZD5069 is a reversible oral CXCR2 antagonist which is under evaluation in inadequately controlled asthma. Methods: The affinity of AZD5069 for CXCR2 and CXCR1 was determined using membranes from HEK293 cells transfected with human recombinant CXCR2 or CXCR1 and a radiolabelled endogenous ligand [I125] CXCL8. The antagonist potency of AZD5069 was also assessed in cell systems, using either CXCL8 or CXCL1 to activate the receptor, quantifying changes in intracellular calcium, CD11b expression and chemotaxis. A rat model of pulmonary inflammation with neutrophilia induced by lipopolysaccharide (LPS) was used to investigate AZD5069 efficacy in vivo . Results: AZD5069 demonstrated high affinity for human recombinant CXCR2 (pIC50 9.1 ± 0.05), a lower affinity for CXCR1 (pIC50 6.9 ± 0.08), potent antagonism of CXCR2-mediated calcium mobilization (pA2 = 9.6 ± 0.1), chemotaxis (pA2 = 9.6) and dose-dependent inhibition of adhesion molecule expression in whole blood. Reversibility was clearly demonstrated by displacement of radiolabelled AZD5069 from CXCR2. In addition, return of CXCR2 activity was shown following removal of AZD5069 from cells. In the LPS in vivo rat model of pulmonary inflammation, oral administration of AZD5069 produced a dose-dependent decrease in lung neutrophilia. Conclusions: AZD5069 is a potent, reversible and selective CXCR2 antagonist that has potential as a new treatment approach for neutrophil driven inflammatory respiratory disorders.